Diazo insertion reactions

McKervey and Ye have developed chiral sulfur-containing dirhodium car-boxylates that have been subsequently employed as catalysts for asymmetric intramolecular C-H insertion reactions of y-alkoxy-ot-diazo-p-keto esters. These reactions produced the corresponding ci -2,5-disubstituted-3(2H)-furanones with diastereoselectivities of up to 47% de. Moreover, when a chiral y-alkoxy-a-diazo-p-keto ester containing the menthyl group as a chiral auxiliary was combined with rhodium(II) benzenesulfoneprolinate catalyst, a considerable diastereoselectivity enhancement was achieved with the de value being more than 60% (Scheme 10.74). 

Rhodium carboxylates have been found to be effective catalysts for intramolecular C—H insertion reactions of a-diazo ketones and esters.215 In flexible systems, five-membered rings are formed in preference to six-membered ones. Insertion into methine hydrogen is preferred to a methylene hydrogen. Intramolecular insertion can be competitive with intramolecular addition. Product ratios can to some extent be controlled by the specific rhodium catalyst that is used.216 In the example shown, insertion is the exclusive reaction with Rh2(02CC4F9)4, whereas only addition occurs with Rh2(caprolactamate)4, which indicates that the more electrophilic carbenoids favor insertion. 

The insertion reaction can be used to form lactones from -diazo-(J-keto esters. 

A second route was devised using chiral /3-keto ester 14, which was identified as our precursor for 2 [7]. This idea was in analogy with the carbapenem chemistry [8], as depicted in Scheme 2.4, where Masamune reaction [9] for carbon elongation, diazo-transfer, and transition metal-mediated carbene insertion reaction [10] were employed as key steps sequentially. 

The use of rhodium(II) acetate in carbenoid chemistry has also been extended to promoting intramolecular C/H insertion reactions of ketocarbenoids 277,280,280 ,). From the a-diazo-P-ketoester 305, highly functionalized cyclopentane 306 could thus be constructed in acceptable yields by regiospecific insertion into an unactivated... 

The photoelimination of nitrogen from diazo compounds provides a simple and versatile route for the generation of carbenes, and in certain instances, insertion reactions of carbenes can be employed in the synthesis of heterocycles. Carbenes are believed to be involved at least in part in the photochemically induced conversion of N,N-diethyldiazoacetamide (439) into the y-lactam 440 and the /Mactam 441,365 and a similar approach has been successfully employed in the synthesis of a carbapen-2-em366 and of 7-methylcephalosporin analogues.367 Carbene insertion of a different type has been observed on irradiation of the 6-anilino-5-diazouracils 442 to give the indolo[2,3-d]pyrimidines 443.368 Ring contractions in heterocycles... 

Alternatively, diazotization of ethyl indole-2-carboxylate (179) leads to formation of 2-carboethoxy-3-diazo-3H-indole (180) which undergoes rhodium-catalyzed alcohol O-H insertion reactions leading to 3-alkoxyindoles 181 <00TL6905>. 

A very impressive application of this chemistry is the total synthesis of (—)-ephedradine A 102.222 The key intermediate /rcarboxylic acid ester 101 was synthesized by intramolecular C-H insertion reaction. Upon treatment with a catalytic amount of Rh2(Y-DOSP)4, aryl diazo ester 100 possessing a chiral auxiliary underwent a C-H insertion reaction to give 101 in 63% yield and 86% de (Equation (83)). 

Using this approach, we have successfully predicted the major product from the cyclization of more than 30 a-diazo esters and a-diazo yS-keto esters [15]. Not all rhodium-mediated intramolecular C-H insertion reactions will proceed to give a single dominant diastereomer. Our interest in this initial investigation was to develop a model for the transition state that will allow us to discern those cyclizations that will proceed with high diastereoselectivity. 

Pirrang, Liu, and Morehead [22] have elegandy demonstrated the application of saturation kinetics (Michaehs-Menten) to the rhodium(II)-mediated insertion reactions of a-diazo /9-keto esters and a-diazo /9-diketones. Their method used the Eadie-Hofstee plot of reaction velocity (v) versus v/[S] to give and K, the equilibrium constants for the catalytic process. However, they were unable to measure the Michaelis constant (fC ) for the insertion reactions of a-diazo esters because they proved to be too rapid. 

A current limitation of the amination methodology is encountered with carbamate esters derived from 2° alcohols (that is, 22 and 24 in Scheme 17.14). With some notable exceptions, substrates in this class often give only small amounts ( 0-20%) of oxazolidinone, and instead afford the corresponding ketones in variable yields. A similar observation has been made by Doyle for C-H insertion reactions with 1-indanol diazo-... 

Working with diazo compounds, known since the early 1900s to undergo loss of dinitrogen when treated with copper or copper salts, Yates described in 1952 the possibility that transition metals could form an intermediate that combined units of the diazo compound and the metal (Eq. 1, L = ligand) and acted like a carbene in addition and insertion reactions. Somewhat later, but independently, E. O. Fischer isolated and characterized stable metal carbenes that could also undergo cyclopro-panation reactions." They were derived from transition metals on the left side of the... 

A variation on the thermal reactions of diazo compounds with alkenes is the decomposition of salts of sulfonylhydrazones. This procedure, known as the BamfoTd-Stevens reaction, is believed to occur via the formation of diazo compounds. Subsequent 1,2-hydrogen shifts generally lead to the formation of alkenes as the final products. Cyclopropanes may also be formed as the result of intramolecular 1,3-C—H insertion reactions or when the original hydrazone substrate contains a remote alkenic group as a site for intramolecular cyclopropanation.10... 

Although C—H insertion reactions rarely occur in intermolecular reactions with diazoacetates, these are common side reactions with diazomalonates3132 (equation 10) and diazo ketones (with a-allyl vinyl ethers).33 Several mechanistic pathways are available to generate the products of an apparent direct C—H insertion reaction and these include dipolar intermediates, ir-allyl complexes and ring opening of cyclopropanes.1 Oxidative problems due to the presence of oxygen are common with copper catalysts, but these are rarely encountered with rhodium catalysts except in systems where the carbenoid is ineffectively captured.34... 

C-H Insertion Reactions, Cycloadditions, and Ylide Formation of Diazo Compounds... 

Asymmetric induction in intramolecular C-H insertion reactions was first reported by McKervey and co-workers [53], who used chiral Rh(II) prolinate 17a (Eq. 5.24). Although enantiocontrol was low, this report established the feasibility of the methodology and left open advances that were subsequently made by Ikegami and Hashimoto, who were able to convert a-diazo-p-ketoester 47 into cyclopentanone 48 with 18a (Eq. 5.25) with 32-76% ee, dependent on the substituent Z and the size of the ester alkyl group [54,116],... 

Although exceptional diastereocontrol and enantiocontrol can now be achieved in C-H insertion reactions of catalytically generated metal carbenes, further improvements are needed. Insertion into tertiary C-H bonds occurs with diminished enantiocontrol and regiocontrol [131,132], In addition, chiral dirhodium carboxamidates do not react with a-diazo-p-ketocar-bonyl compounds. Thus, the potential for their impact on a broad range of C-H insertion processes is yet to be tested. 

Photochemical or copper-catalyzed decomposition of diazo compound 85 failed to give a handle on 2-silanaphthalene 87 (equation 19)49,50. Instead of the expected 1,2-Ph migration, carbene 86 apparently underwent simply an 0,H insertion reaction with methanol in 96% yield. 

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